This invention relates to an angiotensin converting enzyme inhibitor consisting of a peptide having a specified number of amino acid residues containing Val-Pro-Pro as an effective constituent.
The angiotensin converting enzyme, referred to herein as ACE, is mainly present in lungs or vascular endothelial cells and acts on angiotensin I (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu) decomposed by renin to isolate a dipeptide (His-Leu) from its C-terminal end to produce angiotensin II exhibiting a strong vasopressor action. Besides, the enzyme has an action of decomposing and inactivating bradykinin which decreases blood pressure. Since ACE not only produces a peptide which increases blood pressure (angiotensin II) but also decomposes and inactivates a peptide which decreases blood pressure (bradykinin), it exhibits the action of producing a rise in blood pressure. Such consideration has led to development of a variety of substances suppressing a rise in blood pressure by inhibiting such enzymatic activity.
A large number of ACE inhibiting natural and synthetic substances, inclusive of snake venom, have been reported to date. Such synthesized substance as captopril (D-2-methyl-3-mercaptopropanoyl-L-proline) has already been put to practical application as an orally administered vasodepressor. However, such pharmaceutical exhibits side effects in many cases and special attention needs be exercised in safety aspects. ACE inhibitors derived from foodstuff have been studied in many fields in expectation of a vasodepressor exhibiting low toxicity and high safety. For example, ACE inhibiting peptides produced by enzymatic hydrolysis of proteins, such as casein (Susumu Maruyama et al. A. B. C., 51(9), 2557-2561 (1987)), or fish meat protein (by Hiroyuki Ukeda, Nippon Nogei Kagaku Kaishi (Journal of Japan Society for Bioscience, Biotechnology, and Agrochemistry), 66(1), 25-29 (1992)), have been reported to date.
However, those substances supported by effective data obtained by oral administration are only few. Thus, a demand has been raised towards an effective vasodepressor which may be administered orally in a minor dosage with high safety.
Components of lactic acid bacteria have so far been known to exhibit ACE inhibiting capability or an action of producing decreased blood pressure, as reported by Sei Ito in "Medicine and Biology", 116(3), 159-161 (1988) and disclosed in Japanese Laid-Open Patent Publication No. 2-247127. Besides, a high molecular substance with a molecular weight of not less than 5,000 produced by removing microorganisms and casein from fermented milk, has been reported to exhibit an action of producing decreased blood pressure as disclosed in Japanese Laid-Open Patent Publication No. 61-53216. However, only a few reports have been made on ACE inhibitors other than those derived from microorganisms.
Meanwhile, tripeptide Val-Pro-Pro has been synthesized by Rao et al. as a partial constituent of collagen, and reported as being one of substances useful for explanation of racemization (Rao S. Rapaka, R. S. Bhatnagar and D. E. Nitecki, BIOPOLYMERS, 15, 317-324 (1976). However, this substance has not been known to exhibit ACE inhibiting activity. On the other hand, the tripeptide Val-Pro-Pro has been difficult to produce by chemical synthesis. Thus, a demand has been raised towards development of a method for producing such tripeptide easily on an industrial basis.